It has been recognized that the current paradigm of arbitrary and nonspecific delivery of chemotherapeutics can be improved by targeting the activation or release of the chemotherapeutic at a desired site via specific active mechanisms (Moses, et al. (2003) Cancer Cell 4:337-341; Kost and Langer (2001) Adv. Drug Delivery Rev. 46:125-148). Thus, systems that utilize tumor biology have been proposed and utilized to improve the outcome for brain tumor and other cancer patients (Duncan (2003) Nat. Rev. Drug Discovery 2:347-360).
Several aspects of tumor biology have been exploited to utilize tumor biology for delivery of chemotherapeutics, including tissue invasion, angiogenesis, and metastasis. For example, many proteases are implicated in extracellular matrix degradation and matrix metalloproteases have been shown to actively participate in degradation of extracellular matrix and activation of invasion promoting growth factors (Rao, et al. (1996) Clin. Exp. Metas. 14:12-18). Matrix metalloproteases play an important and beneficial role in tissue remodeling, wound healing, and angiogenesis along with negative roles in tumor invasion and neovascularization (Woessner (1991) FASEB J. 5:2145-2154; Mignatti and Rifkin (1993) Phys. Rev. 73:161-185). Unequivocal data confirms that the levels of matrix metalloprotease-2 (MMP-2) and matrix metalloprotease-9 (MMP-9) are observed to increase in correlation with tumor progression in human gliomas (Sawaya, et al. (1996) Clin. Exp. Metas. 14:35-42; Forsyth, et al. (1999) Br. J. Cancer 79:1828-1835). Initial attempts to exploit matrix metalloproteases as a chemotherapeutic target using synthetic matrix metalloprotease inhibitors prevented glioma invasion by inhibiting matrix metalloprotease activity. Matrix metalloprotease inhibitors reduced glioma growth and invasion in vitro and in animal models (Tonn, et al. (1999) Int. J. Cancer 80:764-772; Price, et al. (1999) Clin. Cancer Res. 5:845-854) but have achieved disappointing results in Phase I, II, and III clinical trials (Coussens, et al. (2002) Science 295:2387-2392). Moreover, prodrug activation by MMPs is disclosed in U.S. patent application Ser. No. 09/808,832 and WO 02/072620. Similarly, attachment of therapeutic agents to soluble polymers via MMP-sensitive linkers is disclosed in U.S. patent application Ser. Nos. 10/437,983 and 10/333,619 and U.S. Pat. No. 6,224,903. Moreover, MMP-sensitive linkers are disclosed for preparing biodegradable hydrogel compositions. See U.S. patent application Ser. Nos. 10/385,900.